This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recently, intracellular factors that block human immunodeficiency virus type 1 (HIV-1) infection have been identified, suggesting that innate immunity may play a significant role in restricting HIV-1 infection and replication in the human host and during cross-species transmission. We seek to develop the SIV-macaque model so that we may explore the role of such innate immune factors in restricting retroviral infection and investigate viral evolution and escape in response to these types of factors. Previous studies have shown that simian immunodeficiency virus (SIV) derived from sooty mangabeys (SIVsm) can be successfully transmitted experimentally to rhesus and pig-tailed macaques. Interestingly, we have found that a SIVsm variant that efficiently replicates in pig-tailed macaque CD4+ T-cells and cause disease in the pig-tailed macaque host (SIVmne) can no longer establish infection of T-cells from rhesus macaques. This post-entry block of infection of rhesus T-cells correlates with acquired sensitivity of the virus to restriction by the intracellular innate immune factor TRIM5a. That is, the rhesus TRIM5a protein but not the pig-tail homolog restricts infection by the variant SIVmne. In this proposal, our objective is to examine whether the pig-tailed macaque adapted SIVmne is unable to establish persistent infection of rhesus macaques. The studies will be part of an overall hypothesis that tests whether intracellular innate immune factors determine species-specific infection of macaques by primate lentiviruses. In particular, we will test the hypothesis that a SIVmne that evolved to replicate efficiently in pig-tailed macaques loses the capacity to infect and replicate in rhesus macaques due to the susceptibility to the innate immune factor, TRIM5a. We will test this hypothesis by examining the replication fitness of the SIVmne variant in rhesus macaques (AIM1), and by characterizing the genetic and phenotypic properties of variants that emerge during the course of infection with respect to their sensitivity to restriction by rhesus TRIM5a (AIM2). The results of these studies will help to establish a working model system in which we can experimentally define the significance of the TRIM5a blockade in the host and its potential role in innate immunity against retroviral infection. Ultimately, we hope this information will provide insight into immune mechanisms that may limit or prevent HIV infection and disease.